P-aminobenzene sulfonamides



Patented Feb. 17, 1948 iienryMai-tin. Hans Gysin and Otto Neracher,Basel. and Rudolf Hirt, Riehen, Switzerland, assignors to .l. R. GeigyA. G., Basel, Switzerland, a Swiss firm vNo Drawing. Application May 1.1944. Serial No. 533,658. In Switzerland May 6. 1943 3 Claims;

A process for the (manufacture of p-amino benzene sulfone acylamldes hasbeen described according to which sulfonamides of the benzene series ortheir salts containing in p-position a nitrogen-containing group areinteracted with substituted carboxyllc acids of the benzene series orwith their :functional derivatives being substituted by alkyl and/oralkoxy or alkylthio groups, preferably in the presence of catalysts oracid binding agents. and .the p-positioned nitrogen group is eventuallyconverted into an aminoggroup. Furthermore, the above described processhas been extended to highly alkylated carboxylic acids of the benzenes'eriesas well as to carboxylic acids with condensed nuclei, lwhichcarboirylic ac ds are involved in the acylation.

Whereas hitherto exclusively compounds with aromatic or cycliccarboxylic acids have been described, we have now found thatindifferently substituted cinnamic acids are also very suitable for :thesame purposes. As inert substituents maybe understood those which are:not capable of forming salts, that is to say which do not possess amanifest polar character, suchas for instance halogens, alkoxy,.aryloxy, alkyl, ,aryl groups. etc.-; these substituents may .be presenteither in the aliphatic or aromatic portion of the cinnamic acid:molecule. The new compounds diirer from ether acy-lat d:p-amino-benzenesmfonamides by their efiicacy in checking thedevelopment of tubercle-bacilli.

As sultonamides cfthe benzene series containing :a nitrogen-containinggroup in p-position to the sulfonamide group there maybe cited:paminobenzene sulfcnamide, p-acylaminobenzene sul-fonamide,,p-nitrobenzene sulfonamide and the like. Instead ,of the nitro gg-IOHDany-other group convertible by reduction into the amino group may beused, such as for example the nitroso, azo, azoxy or hydrazo group.Azomethine and acylamino groups may be converted into amino groups'byhydrolysis. Advantageously those-acyl radicals are selected which canagain easily be split off. As such radicals the following may forexample b enumerated: the acetyl or carbomethoxy radical which are againeasily split'oflf by a hydrolytical treatment without changing theacylated sulfonamide group.

The present invention will now be illustrated but not limited by thefollowing examples, the parts being by weight.

EXAMPLE "1 38,9 parts of 3 :4-dimethy l cinnamoyl chloride are treatedwith 200 parts of chlorobenzene, "2

parts of copper powder and 42.8 parts of pacetylaminobenzene sultonamideand the whole is boiled under reflux for 6 hours. The reaction mass isthen introduced into a dilute sodium carbonate solution and filteredafter cooling. The chlorobenzene is blown off by means of steam and theaqueous solution is acidified. The raw acetyl compound is reprecipitatedin a sodium carbonate solution and heated under reflux for 1 hour with20 parts of sodium hydroxide in parts of water. After dilution withwater the mixture is acidified, whereby the 4-aminobenzene-N-i3z 4dimethylcinnamoyl)-sulfamide is precipitated. After -reprecipitation bymeans of a sodium carbonate solution in the presence of animal charcoal,the new compound is recrystallised from water and alcohol. Its meltingpoint is C. (under decomposition).

According to the same method the analogous compounds with the acylradical may be produced (M. P. 209 210 0.).

Instead of the acid enumerated above the following carboxylic acids ortheir deivatives can be used, whereby bodies with similar properties areobtained: oand m-methylcinnamic acid, 3 :5-dimethylcinnamic acid, 3 45-trimethylcinnamic acid, p-ethylcinnamic acid, p-isopropylcinnamicacid, p-propylcinnamic acid, pisobutylcinnamic acid, tertiarybutylcinnamic acid and the like; 0-, mand p-chlorocinnamic acid,2:4-dichlorocinnamic acid, 2: -dichlorocinnamic acid,3:4-dichlorocinnamic acid, 2:3:4- trichlorocinnamic acid2:4:5-trichlorocinnamic acid, 6110;; 4-methoxycinnamic acid, 4-ethoxycinnamic acid, 4-isopropoxycinnamic acid, etc.; 3 l-dimethoxycinnamicacid, 2 3-dimethoxycinnamic acid, 2:4-dimethoxycinnamic acid, 2:4-diethoxycinnamic acid, 3:4-methylene dioxycinnamic acid,4-phenoxycinnamic acid, etc.

EXAMPLE 2 48.5 parts of a-phenylcinnamoyl chloride are dissolved in 200parts of chlorobenzene, then 2 partsofoopper powder and 42.8parts ofp-acetylaminobenzenesulfonamlde are added thereto and the whole isheated for 12 hours to -135-140 C. After dissolution in a warm sodiumcarbonate solution the 'organicsolvent is separated in theseparating-funnel. The aqueous-solution is clarilied and treated with anexcess of hydrochloric acid, the 'acetyl compound being thus pre-'cipitated. Without further purification the lattolylcinnamic acid,d-(p-chlorophenyl)-cinnamic acid, a-(p-methoxyphenyl) -cinnamic acid,oc- (3z4-dimethoxyphenyl) -cinnamic acid, etc.

EXAMPLE 3 40.4 parts of p-nitrobenzene sulfamide are suspended in 200parts of pyridine -nd. while stirring, 41.3 parts of B-propylcinnamoylchloride are caused to drop thereinto. Then the mixture is heated forone hour on the water-bath, whereupon the solution is introduced understirring into diluted hydrochloric acid; the little quantities of resinthus resulting are separated (by reprecipitation from sodium carbonatesolution by means of hydrochloric acid) and the remaining mixture isreduced according to Bchamp. By recrystallisation from water and alcoholthe 4- aminobenzene-N-(B propylcinnamoyl) sulfonamide of the meltingpoint of 160-162 C. is obtained.

According to the same process the analogous compounds may be preparedwith the following EXAMPLE 5 42.9 parts of p-chloro p-methylcinnamoylchloride are dissolved in 200 parts of chlorobenzene or of anotherorganic solvent and heated under reflux'for 6 hours with 2 parts ofcopper powder and 42.8 parts of p-acetylaminobenzene sulfonamide. Thechlorobenzene is blown off by means of steam, the residue dissolved in asodium car bonate solution, filtered and the acetyl derivative isprecipitated with mineral acid. Then the raw product is saponified with2n caustic soda lye and the pure4-aminobenzene-N-(p-chloro-B-methylcinnamoyl) -sulfonamide having themelting point of 192-194 C. is obtained therefrom by recrystallisationfrom alcohol and water.

The following table contains further combinations of analogous compoundswith diflerent acyl radicals.

Table 3' ecyl radical 2 on? =on.o 0- 194 195 3 CHr-C -C=CH.CO 195-191acyl radicals:

' T "Jae A No. acyl radical V M. P

(EH: 1 -c=cn.o oi64l65 c.

2 CH=(|J.C 0- 156158 0.

3 (IJ=(IJ.C 0- not crystallisable. CH3 CH3 4 -s==s.c o- 130 c.

CH: CzHt Beside the acid mentioned in the Example 3 and in Table A thefollowing carboxylic acids may also be used: c-ethylcinnami acid,a-ethylcinnamic acid, a-propylcinnamic acid, a-mfithYl-fi-ethYlcinnamicacid, azfi-diethylcinnamic acid, etc.

EXAMPLE 4 20.2 parts of p-nitrobenzene sulfonamide in 200 parts ofchlorobenzene are heated to boiling for 5 hours under stirring with 21parts of p-methoxy-p-methylcinnamoyl chloride and 1 part of copperpowder. Then the solvent is removed by means of steam, the residuedissolved in a sodium carbonate solution, filtered and the nitroderivative freed by means of acid. By reduction of the nitro bodyaccording to Bchamp the 4-aminobenzene-N-(p-methoxy 5 methylcinnamoyD-sulfamide is obtained which, when recrystallised from water and alcohol,possesses the melting point of 1.82-184 C.

Beside the compounds cited in the Examples In this application, onlyB-alkyl-cinnamoylsulfanilamides are claimed. The analogous 4- alkylanda:fi-dialkyl-cinnamoyl-sulfanilamides are claimed in our copendingapplication, Ser. No. 752,558, filed June 4, 1947.

What we claim is: s

1. A p-amino-benzene sulfonamide of the formula ower alkyi wherein Arrepresents a member selected from the group consisting of phenyl.p-tolyl. p-methoxyphenyl, p-chlorophenyl and 3:4-dimethylphenylradicals. 1

6 o c. 0330' =CH. C 0- isosl 5 6 2. The p-aminobenzene-sultonamlde ofthe rar- REFERENOES CITED mula The following references are of record inthe mNOsor-NH-c 0-cH=c-C cm file 01' this patent:

$11. 5 FOREIGN PATENTS 3. The p-aminobenzene sulfonamide of the for-Number Country Date mula 111,230 Australia Aug, 22, 1940 HINOSOPNH C O10 OTHER REFERENCES v Crossley et aL, Jour. Am. Chem. 800., vol. 61,

CH: HENRY MARTIN, Och 1939, pp. 2950-2955.

HANS GYSIN. O'I'I'O NERACHER. RUDOLF HIR'I. ll

